Discovery and Optimization of 4-Aminopteridin-7(8 <i>H</i> )-one Derivatives as Potent and Selective mTOR Inhibitors with Favorable Pharmacodynamic and Safety Characteristics

The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and a promising cancer therapeutic target. Using structure-guided design, we developed novel 4-aminopteridin-7(8<i>H</i>)-one derivatives as ATP-competitive mTOR inhibitors. The lead compound T133 (<b>51</b>) demonstrated exceptional mTOR inhibition (<i>K_i</i> = 0.17 nM) with high selectivity, effectively suppressing phosphorylation of downstream effectors, such as AKT, S6K1, and 4EBP1. In HGC-27 gastric cancer cells, T133 potently inhibited proliferation and migration while inducing apoptosis, cell cycle arrest, and autophagy. This efficacy extended to NCI-H1299 lung cancer and T-47D breast cancer cells. In the HGC-27 xenograft mouse model, oral administration of T133 exhibited dose-dependent efficacy comparable to clinical-stage inhibitor PF-04691502, while exhibiting significantly reduced hepatotoxicity, nephrotoxicity, and pulmonary toxicity. Moreover, assessments of T133 on cytochrome P450, hERG, and AMES indicate a favorable safety profile. These findings suggest T133 is a promising mTOR inhibitor, warranting further investigation for cancer therapy.